1,3-enynes can be found in many naturally occurring and biologically active compounds. Terbinafine, which is commonly known as Lamisil®, contains the 1,3-enyne moiety and is a pharmaceutically important compound used in the treatment of superficial fungal infections. Another pharmaceutically important compound is Calicheamicin γ1I which has been shown to be an effective antitumor antibiotic. 1,3-enynes are also important precursors to polysubstituted benzenes and conjugated dienes via hydroboration-protonolysis.
Among the methods developed to synthesize 1,3-enynes, the Pd—Cu catalyzed Sonogashira coupling reaction between an alkyne and a vinyl halide is most prevalent. Other methods include the Pd-catalyzed coupling between a terminal organometallic alkyne (Cu, Mg, Si, Zn, Sn) and an alkene or the alkynylation of alkenyl metals (Al, B, Cu Mg, Zr). The latter methods do suffer from some drawbacks such as use of toxic reagents, the need to prepare an organometallic alkyne or alkene, poor functional group tolerance, and undesired side-products resulting in low yields.
Various concerns in the art, however, continue to prompt development of new catalytic systems. In particular, the price of palladium is prohibitive, having risen by about 900% in recent years. Further, expensive ligands are required for the palladium reactions of interest. As a result, alternate metals and ligand systems have been the subject of increased study. One such approach uses copper to mediate the synthesis of conjugated enynes: for instance, 1,3-enynes by coupling trimethylsilyl alkynes with vinyl iodides. However, this procedure requires the use of a greater than stoichiometric amount of CuCl and is limited to propargylic alcohol derivatives. Conjugated enynes have also been prepared through the coupling of alkenyldialkylboranes and (trimethylsilyl)ethynyl bromide using catalytic Cu(acac)2, but only by using strong bases such as NaOMe and LiOH. As a result, the development of copper-based protocols for such cross-coupling reactions remains an on-going concern in the art.